Jump to

Abstract

Plaque vulnerability is the critical factor for the onset of acute coronary syndrome. Here we show that ARIA, a gene that we recently identified as a regulator of endothelial apoptosis, provides a previously undescribed molecular pathway that modifies the plaque vulnerability. ER stress-induced macrophage apoptosis in the advanced atherosclerotic lesion plays a crucial role in the formation of vulnerable plaque. Currently, we found that ARIA expression was substantially enhanced in macrophages by the ER stress, which urged us to study a role of ARIA in the ER stress-induced macrophage apoptosis and the plaque vulnerability. We previously reported that ARIA negatively regulates the expression of inhibitor of apoptosis (cIAP)-1 and -2 in endothelial cells. cIAPs are known to play an essential role in the macrophage survival, and we found that overexpression of ARIA in macrophages significantly reduced the cIAPs expressions and consequently enhanced their susceptibility to apoptosis. In contrast, ARIA-silencing significantly ameliorated the ER stress-induced macrophage apoptosis. Of note, ER stress reduced the cIAPs expressions in macrophages, which was abolished by the shRNA-mediated ARIA-silencing. These indicate that ER stress induces ARIA expression in macrophages, and ARIA in turn accelerates the macrophage apoptosis by reducing the cIAPs. To further investigate the role of ARIA in the plaque vulnerability, we generated mice with targeted deletion of both ARIA and ApoE (DKO). Mice were fed a high-cholesterol diet for 15 weeks to form the advanced atherosclerotic plaque. Interestingly, modest reduction in plaque size was observed in DKO mice comparing with ApoE-KO mice. Moreover, DKO mice showed significantly less necrotic core formation, increased collagen content and thick fibrous cap in the plaque, indicating the invulnerable plaque comparing with those in ApoE-KO mice. In the plaque of DKO mice, we detected less TUNEL-positive apoptotic cells and more macrophages than those in the plaque of ApoE-KO mice. Together, we identified a crucial role of ARIA in the plaque vulnerability through a control of macrophage apoptosis, and thus ARIA offers a unique therapeutic potential in the treatment of atherosclerotic diseases.